This proposal describes the design and evaluation of new conjugates of synthetic human E. coli ST (STh) peptides that form high specific activity site-directed radiopharmaccuticals for selective in vivo targeting of colorectal neoplasias that express guanylin/guanylate cyclase-C (GC-C) receptors. Diagnostic or therapeutic radiopharmacouticals that result from this work will be labeled with 11In, 90Y, 149Pm or 177Lu, radionuclides that are available as no-carrier-added (NCA) reagents that have half-lives compatible for preparing radiometallated receptor-avid peptide conjugates. The specific objectives of this research are to: 1) synthesize new DOTA-X-Phe19-STh analogues that exhibit high specific binding affinities with human colon cancer cells expressing GC-C receptors; 2) use normal and tumor-bearing animal models to identify radiolabeled peptides that exhibit optimal in vivo pharmacokinetics and tumor uptake and residualization properties; 3) evaluate the diagnostic or therapeutic efficacy of the most promising DOTA-X-Phe19-STh constructs when labeled with. 111In or with 90Y, 149Pm and 177Lu for controlling or ablating human LS-180/T-84 colon cancer cell derived tumors in SCID mice. The new DOTA-X-Phe19-STh (X=spacer group) and the corresponding 111In, 90Y, 149Pm and 177Lu labeled conjugates will be synthesized, purified and characterized at both macroscopic and tracer levels. The experimental approaches used in the proposed research are designed to characterize structures that maximize cancer cell uptake and GC-C receptor-mediated intracellular residualization. The ability to synthesize predetermined tether (X) sequences linking DOTA and Phe19-STh also enables identification of conjugate constructs that minimize residualization of activity in critical non-target organs or tissues. The results of these studies should provide DOTA-X-Phe19-STh analogues that, when labeled with 111In+3, 90Y+3, 149Pm+3, 177Lu+3 and potentially other radiometals, could be developed (via future FDA approved clinical trials) into effective radiopharmaccuticals for monitoring or treatment of patients with colonic neoplasias overexpressing GC-C receptors.